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Comprehensive Summary: Five unreported and oxygenated ent‐rosane diterpenoids (ent‐RDs), Euphomillanols A—E (1—5), were isolated from Euphorbia milii. Among them, compounds 1 and 2 are unprecedented 7/7/6‐fused tricyclic 5,10‐seco‐ent‐RDs and possess a unique 11‐oxabicyclo[4.4.1]undeca‐1(10),5‐diene moiety, while 3 is characterized by a 1‐methyl‐6‐oxabicyclo[3.2.1]oct‐2‐ene motif of ring A. Their structures with absolute configurations were unambiguously determined by the extensive spectroscopic methods, X‐ray crystallography, and ECD calculation. Putative biosynthetic pathways for compounds 1—3 are proposed. All compounds exhibited antiadipogenic effects in 3T3‐L1 adipocytes, and the most potent compound 4 showed an EC50 value of 3.92 μmol/L with low cytotoxicity (IC50 > 89.54 μmol/L). [ABSTRACT FROM AUTHOR]

Chlororaphens A and B are structurally unique non‐canonical C17 sesquiterpenoids from Pseudomonas chlororaphis that are made by two SAM‐dependent methyltransferases and a type I terpene synthase. This study addresses the mechanism of their formation in isotopic labelling experiments and DFT calculations. The results demonstrate an astonishing complexity with distribution of labellings within a cyclopentane core that is reversely connected to two acyclic fragments in chlororaphen A and B. In addition, the uptake of up to 14 deuterium atoms from D2O was observed. These findings are explainable by a repeated late stage multistep rearrangement sequence. The absolute configurations of the chlororaphens and their biosynthetic intermediates were elucidated in stereoselective labelling experiments. [ABSTRACT FROM AUTHOR]

In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA‐H) and salts of sodium (‐Na), calcium (‐Ca), ammonium (‐NH4), triethylammonium (‐TEA), tris(hydroxymethyl)aminomethane (‐Tris), benethamine (‐Bnet), and benzathine (‐BZ) were prepared. Their solid‐state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot‐stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X‐ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA‐BZ featured the lowest aqueous solubility and hygroscopicity, with 50 μg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X‐ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP‐ conformation at the phosphorus atom. [ABSTRACT FROM AUTHOR]

Domino Knoevenagel‐cyclization reactions of 2H‐chromene and chroman derivatives containing o‐formylaryl amine or ether side‐chain was carried out to produce four series of chiral condensed heterocycles representing four novel skeletons and exhibiting antiproliferative activity. The cyclization step occurred with four different mechanisms: a concerted intramolecular hetero Diels‐Alder reaction (IMHDA), a stepwise polar [2+2] cycloaddition, a [1,5]‐hydride shift‐6‐endo cyclization or a multi‐step nitro hetero Diels‐Alder‐ring‐opening‐Cadogan‐type cyclization sequence. The latter reaction provided a new route to hydroxyindoles by an inverse Cadogan‐type cyclization, in which the nitro group is deoxygenated by a nitro IMHDA‐ring‐opening sequence. The cyclization mechanisms and their stereoselectivity were studied by DFT calculations, based on which we proposed a mechanism for the multi‐step cyclization to hydroxyindoles and explained the observed diastereoselectivity. [ABSTRACT FROM AUTHOR]

Abstract In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA‐H) and salts of sodium (‐Na), calcium (‐Ca), ammonium (‐NH4), triethylammonium (‐TEA), tris(hydroxymethyl)aminomethane (‐Tris), benethamine (‐Bnet), and benzathine (‐BZ) were prepared. Their solid‐state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot‐stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X‐ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA‐BZ featured the lowest aqueous solubility and hygroscopicity, with 50 μg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X‐ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP‐ conformation at the phosphorus atom.

Germacranes are important intermediates in the biosynthesis of eudesmane and guaiane sesquiterpenes. After their initial formation from farnesyl diphosphate, these neutral intermediates can become reprotonated for a second cyclisation to reach the bicyclic eudesmane and guaiane skeletons. This review summarises the accumulated knowledge on eudesmane and guaiane sesquiterpene hydrocarbons and alcohols that potentially arise from the achiral sesquiterpene hydrocarbon germacrene B. Not only compounds isolated from natural sources, but also synthetic compounds are dicussed, with the aim to give a rationale for the structural assignment for each compound. A total number of 64 compounds is presented, with 131 cited references.

Fourteen undescribed nitrogenous merosesquiterpenoids, purpurols A−D (1 – 4) and puraminones A−J (5 – 14), along with three known related compounds (15 – 17) were isolated from the sponge Pseudoceratina purpurea collected in the South China Sea. Their structures and absolute configurations were unambiguously elucidated by a combination of spectroscopic data, X-ray diffraction analysis, electronic circular dichroism calculations, and chemical derivatization. Purpurols A−D (1 – 4) incorporated nitrogenous heterocycles, compounds 1 and 2 feature an unusual benzothiazole ring, while 3 and 4 feature benzoxazole ring. Puraminones A−J (5 – 14) represent sesquiterpenoid aminoquinones with different amine and amino acid side chains at C-20. Additionally, twenty unreported sesquiterpenoid aminoquinone analogues were obtained through chemical derivatization. It is worth noting that all compounds are featured with unusual rearranged 4,9-friedodrimane subunit. In the bioassays, purpurols A and B showed weak anti-inflammation in zebrafish, as well as some compounds showed activities against tumor cells, therefore, preliminary structure–cytotoxicity relationships are also discussed. [Display omitted] • Fourteen undescribed nitrogenous merosesquiterpenoids were reported. • Their structures were elucidated by NMR, ECD, chemical derivatization, and X-ray diffraction. • Compounds 1 and 2 showed weak anti-inflammation in zebrafish. • Compounds 5 , 9 , 10 , and 14 showed moderate cytotoxicity against K562 cell lines. [ABSTRACT FROM AUTHOR]

Two analogues of the diterpene precursor geranylgeranyl diphosphate with shifted double bonds, named iso‐GGPP I and iso‐GGPP II, were enzymatically converted with twelve diterpene synthases from bacteria, fungi and protists. The changed reactivity in the substrate analogues resulted in the formation of 28 new diterpenes, many of which exhibit novel skeletons. [ABSTRACT FROM AUTHOR]

Chlororaphens A and B are structurally unique non-canonical C 17 sesquiterpenoids from Pseudomonas chlororaphis that are made by two SAM-dependent methyltransferases and a type I terpene synthase. This study addresses the mechanism of their formation in isotopic labelling experiments and DFT calculations. The results demonstrate an astonishing complexity with distribution of labellings within a cyclopentane core that is reversely connected to two acyclic fragments in chlororaphen A and B. In addition, the uptake of up to 14 deuterium atoms from D 2 O was observed. These findings are explainable by a repeated late stage multistep rearrangement sequence. The absolute configurations of the chlororaphens and their biosynthetic intermediates were elucidated in stereoselective labelling experiments., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Comprehensive Summary: Seven new kalihinene diterpenoids, kalihioxepanes A—G (1—7) bearing a rare oxepane ring, were isolated from sponge Acanthella cavernosa collected from the South China Sea. The structures and absolute configurations were elucidated by comprehensive spectroscopic analysis, single crystal X‐ray diffraction, and quantum chemical calculation methods. Kalihioxepane A (1) displayed strong cytotoxicity against H69 and K562 tumor cells, while kalihioxepane B (2) showed moderate cytotoxicity against K562 cells. [ABSTRACT FROM AUTHOR]

The marine natural product hemicalide displays potent anticancer activity. While detailed NMR experiments established the planar carbon skeleton, its full configurational assignment proved enigmatic. This Review summarises ongoing synthetic efforts and NMR studies on hemicalide, which have succeeded in reducing the number of possible stereoisomers from more than one million to a more manageable eight structures, setting the stage for a focused total synthesis campaign. [ABSTRACT FROM AUTHOR]

A previously undescribed open-loop decarbonizing cembranolide, sarcocinerenolide A, and eight undescribed cembranolides, sarcocinerenolides B–I, characterized by poly-membered oxygen ring fragments were isolated from the soft coral Sarcophyton cinereum collected from the South China Sea. The structures and absolute configurations of these previously undescribed compounds were precisely determined by analysis of NMR data, DP4+ and ECD spectra. The bioactivities of the compounds were evaluated using zebrafish models and sarcocinerenolides C and H exhibited anti-thrombotic activity. [Display omitted] • One decarbonizing and eight polyoxygenated cembranolides were reported. • The structures were determined by analysis of NMR data, DP4+ and ECD spectra. • Compounds exhibited anti-thrombotic activity. [ABSTRACT FROM AUTHOR]

A new cembrane-type diterpenoid, named iso-ximaonanolobatin G (1), and one known related one, namely ximaonanolobatin G (2), along with four known steroids, were isolated from the South China Sea soft coral Sinularia nanolobata. Their full structures were elucidated by extensive spectroscopic analysis, quantum mechanical (QM)-NMR methods, and by the comparison of the spectroscopic data with those reported in the literature. [ABSTRACT FROM AUTHOR]

The known sesquiterpenes that arise biosynthetically from hedycaryol are summarised. Reasonings for the assignments of their absolute configurations are discussed. The analysis provided here suggests that reprotonations at the C1=C10 double bond of hedycaryol are directed toward C1 and generally lead to 6–6 bicyclic compounds, while reprotonations at the C4=C5 double bond occur at C4 and result in 5–7 bicyclic compounds. Read more in the Review by H. Xu and J. S. Dickschat (DOI: 10.1002/chem.202200405). [ABSTRACT FROM AUTHOR]

Five analogs of dimethylallyl diphosphate (DMAPP) with additional or shifted Me groups were converted with isopentenyl diphosphate (IPP) and the fungal variediene synthase from Aspergillus brasiliensis (AbVS). These enzymatic reactions resulted in the formation of several new terpene analogs that were isolated and structurally characterised by NMR spectroscopy. Several DMAPP analogs showed a changed reactivity giving access to compounds with unusual skeletons. Their formation is mechanistically rationalised and the absolute configurations of all obtained compounds were determined through a stereoselective deuteration strategy, revealing absolute configurations that are analogous to that of the natural enzyme product variediene. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Ten new cembrane‐type diterpenoids, namely xishaglaucumins A—J (1—10), along with ten known related ones (11—20), have been isolated from the soft coral Sarcophyton glaucum collected off the Xisha Island in the South China Sea. Their structures were elucidated by extensive spectroscopic analysis, quantum mechanical nuclear magnetic resonance (QM‐NMR) methods, X‐ray diffraction analysis, chemical methods and comparison with the reported data in the literature. The absolute configuration of new compounds 1, 5 and known compounds 11, 12, 16 and 20 were determined either by chemical methods or by X‐ray diffraction analysis using Cu Kα (λ = 1.5417 Å). In in vitro bioassay, compound 4 exhibited inhibitory effects on lipopolysaccharide (LPS)‐induced inflammatory responses in BV‐2 microglial cells. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: In the present study, nine new cembrane‐type diterpenoids, namely ximaonanolobatins A—I (1—9), together with six related known analogs (10—15) and four known tetraprenylated alkaloids malonganenones D, E, H, and K (16—19) were isolated from the soft coral Sinularia nanolobata collected off the Ximao Island in the South China Sea. The structures of 1—9 were robustly established by a combination of detailed spectroscopic analyses, chemical reactions, quantum mechanical (QM)‐NMR methods, biogenetic consideration, and the comparison with those literature data. The absolute configuration of 1 was confirmed by X‐ray diffraction analysis, and the absolute configuration of 2 was determined by QM‐NMR calculations and chemical transformation. In addition, the absolute configuration of 3 was determined using the modified Mosher's method. All these isolates were evaluated for their anti‐inflammatory and anti‐tumor activities. The results showed that only compound 15 exhibited potential anti‐inflammatory effect against LPS‐induced TNF‐α release in RAW264.7 macrophages with an IC50 value of 12.6 μmol/L. [ABSTRACT FROM AUTHOR]

There are marine cytotoxic bromotriterpenoids, named the thyrsiferol family that are structurally characterized by some tetrahydropyran (THP) and tetrahydrofuran (THF) rings. The thyrsiferol family belongs to natural products that are often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic tetrasubstituted carbon centers. In such cases, it is effective to predict and synthesize the possible stereostructures. Herein, to elucidate ambiguous stereostructures and unassigned absolute configurations of aplysiol B, laurenmariannol, and saiyacenol A, members of the thyrsiferol family, we carried out their asymmetric chemical syntheses featuring 6‐exo and 5‐exo oxacyclizations of epoxy alcohol precursors and 6‐endo bromoetherification of a bishomoallylic alcohol. In this paper, we report total assignments of their stereostructures through their asymmetric chemical syntheses and also their preliminary cytotoxic activities against some tumor cells. These results could not have been achieved without depending on asymmetric total synthesis. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: A phytochemical investigation on the seeds of Sophora alopecuroides led to obtaining fourteen structurally diverse matrine‐based alkaloids (1—14), including eight new ones (1, 6, 8—12, 14). Notably, alopecuroide F (1) represents the first dimeric matrine‐type skeleton assembled via unprecedent C‐13–C‐12' connection. The new structures were determined through extensive spectroscopic data (UV, OR, HRESIMS, 1D, and 2D NMR), ECD calculations, and three instances, verified by X‐ray crystallography. Biologically, all alkaloids were evaluated for cytotoxicity against four human cancer cell lines (HepG2, A549, THP‐1, and MCF‐7) and anti‐inflammatory activities for two pro‐inflammatory cytokines (TNF‐α and IL‐6). Alopecuroide F (1) can inhibit TNF‐α and IL‐6 productions in a dose‐dependent manner, with IC50 values of 35.6 ± 0.5 and 41.7 ± 0.8 μmol/L, respectively. [ABSTRACT FROM AUTHOR]

Four synthetic farnesyl diphosphate analogues were enzymatically converted with three bacterial sesquiterpene synthases, including β‐himachalene synthase (HcS) and (Z)‐γ‐bisabolene synthase (BbS) from Cryptosporangium arvum, and germacrene A synthase (SmTS6) from Streptomyces mobaraensis. These enzyme reactions not only yielded several previously unknown compounds, showing that this approach opened the door to a new chemical space, but substrates with blocked or altered reactivities also gave interesting insights into the cyclisation mechanisms and the potential to catalyse reactions with different initial cyclisation modes. [ABSTRACT FROM AUTHOR]

The regio‐selective four step synthesis of (1S,2R,3S,4R)‐4,7,7‐trimethyl‐3‐(neopentyloxy)bicyclo[2.2.1]heptan‐2‐ol, as recognized efficient chiral auxiliary, is presented. The strategy based on opening of the key acetal 15 (=(2S,3aR,4S,7R,7aS)‐2‐tert‐butyl‐4,8,8‐trimethylhexahydro‐2H‐4,7‐methano‐1,3‐benzodioxole) thus circumvents the poor reactivity of the neopentyl electrophile under alkylation conditions. Following the same strategy, but using the unreported acetal 22 (=(2R,3aS,4S,7R,7aR)‐2‐tert‐butyl‐4,8,8‐trimethylhexahydro‐2H‐4,7‐methano‐1,3‐benzodioxole), the corresponding unreported bis‐endo alcohol 23 (=(1R,2R,3S,4S)‐3‐(2,2‐dimethylpropoxy)‐4,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐ol) could be isolated only in poor yield. An alternative regioselective synthesis, including an ultimate endo‐reduction remains to be found. Several erroneous chiroptical properties from the literature are corrected. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: A detailed chemical study on the Hainan soft coral Sinularia crass has resulted in the isolation and characterization of eleven casbane‐type diterpenoids, named sinucrassins A—K (1—11), along with six known related ones (12—17). Their structures were elucidated by extensive spectroscopic analyses and comparison with the reported data. The absolute configurations of new compounds were determined by the X‐ray diffraction analysis and computer‐assisted structural elucidation including 13C NMR data calculation and time‐dependent density functional theory/electronic circular dichroism calculation. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: A rare highly fused racemic merosesquiterpenoid, 9‐epi‐verrubenzospirolactone (1), six new asteriscane‐type sesquiterpenoids, sinuhumesins A—F (4—9), and two related known ones (10 and 11) were isolated from Hainan soft coral Sinularia humesi. Compound 1 was further separated by chiral HPLC resolution to one pair of enantiomers [(+)‐1 and (–)‐1], respectively. The full structures of the new compounds were unambiguously determined by extensive spectroscopic analysis, chemical computation approaches, modified Mosher's method and/or X‐ray diffraction analysis, as well as comparison with previously reported data of related model compounds. [ABSTRACT FROM AUTHOR]

The demand for more efficient methods of establishing the undetermined stereochemistries of peptidic natural products continues unabated. A new method for microscale stereochemical determination was devised by integrating solid‐phase synthesis, split‐and‐mix randomization, 18O/16O‐encoding of d/l‐configurations, tandem mass spectrometry, and biological evaluation. Here we applied gramicidin A as the molecule for a blind test. Gramicidin A and its 31 diastereomers were randomly prepared in microgram scale with 18O/16O‐stereochemical encoding and subjected to MS/MS‐structural determination and cytotoxicity assay. Only the parent gramicidin A was selected from among the 32 stereoisomers, validating the high reliability of the present strategy. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: A rare highly fused racemic merosesquiterpenoid, 9‐epi‐verrubenzospirolactone (1), six new asteriscane‐type sesquiterpenoids, sinuhumesins A—F (4—9), and two related known ones (10 and 11) were isolated from Hainan soft coral Sinularia humesi. Compound 1 was further separated by chiral HPLC resolution to one pair of enantiomers [(+)‐1 and (–)‐1], respectively. The full structures of the new compounds were unambiguously determined by extensive spectroscopic analysis, chemical computation approaches, modified Mosher's method and/or X‐ray diffraction analysis, as well as comparison with previously reported data of related model compounds. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: Two new bis‐quinolizidine alkaloids, neopetrosiasins A (1) and B (2), possessing cis‐ and trans‐quinolizidine nuclei, one known related analogue petrosin (3) and three known xestospongins (4—6), were isolated from the South China Sea sponge Neopetrosia chaliniformis. The structures of new compounds were unambiguously determined by extensive spectroscopic and single‐crystal X‐ray analyses. In bioassay, compounds 4—6 exhibited moderate cytotoxicity against several human cancer cells. [ABSTRACT FROM AUTHOR]

Four new guaiane-type sesquiterpenes, argyin H–K (1–4), and two known analogues (5 and 6) were isolated from the leaves of Artemisia argyi Lévl et Vant. The new compounds were characterized by the basic analysis of the spectroscopic data obtained (1H NMR, 13C NMR, HMBC, and NOESY experiments), and their absolute configurations were determined by empirical approaches, combined with the exciton chirality method and electronic circular dichroism calculations. To further understand the antitumor effects of A. argyi, the antiproliferative activities of these compounds against A549, MCF-7, and HepG2 cell lines were tested in vitro using CCK-8 assays. The results showed that these compounds had significant antiproliferative effects on MCF-7, with IC50 values of 15.13–18.63 μM, which were superior to that of oxaliplatin (i.e., IC50 22.20 μM).

Nineteen polyoxygenated eunicellin diterpenoids, named klyflaccilins B‐T (1–19), were isolated from the South China Sea soft coral Klyxum flaccidum. Their structures were established by extensive spectroscopic analysis and for several of the isolated compounds the absolute configurations were determined by X‐ray diffraction analysis. [ABSTRACT FROM AUTHOR]

This review summarises known sesquiterpenes whose biosyntheses proceed through the intermediate germacrene A. First, the occurrence and biosynthesis of germacrene A in Nature and its peculiar chemistry will be highlighted, followed by a discussion of 6–6 and 5–7 bicyclic compounds and their more complex derivatives. For each compound the absolute configuration, if it is known, and the reasoning for its assignment is presented. [ABSTRACT FROM AUTHOR]

The crystalline sponge (CS) method allows structural elucidation of a target compound (guest) in solution by single crystal X‐ray diffraction through trapping the guest into the CS framework. In principle, the CS method is inapplicable to reactive compounds that break the CS framework, such as acidic, basic, or nucleophilic ones. Here, a solution to this problem is disclosed wherein an ion pair of the guest compound is formed during the guest‐soaking step by adding a suitable reagent. The ion pair can be observed and does not damage the CS framework. Using the developed method, amino, guanidino, and amidino compounds have been successfully analyzed as ion pairs with sulfonic acids. Practical utility has been shown because the absolute configurations of optically resolved amine derivatives were revealed with only a few micrograms. This demonstrates that the ion‐pair‐soaking method is simple and expands the range of compounds applicable to the CS method. [ABSTRACT FROM AUTHOR]

A biosynthetic gene cluster from Streptomyces mobaraensis encoding the first cases of a bacterial geranylfarnesyl diphosphate synthase and a type I sesterterpene synthase was identified. The structures of seven sesterterpenes produced by these enzymes were elucidated, including their absolute configurations. The enzyme mechanism of the sesterterpene synthase was investigated by extensive isotope labeling experiments. [ABSTRACT FROM AUTHOR]

Knowledge of absolute configurations (ACs) is crucial to understand the properties and functions of chiral molecules. Although the development of asymmetric reactions has enabled access to a large variety of enantioenriched compounds, stereochemical assignments of chiral molecules, especially chiral alkanes, remain challenging. In this Minireview, we first summarize common analytical techniques for AC determination with a focus on chiral alkanes as analytical targets. Next, we describe some of our efforts over the last 20 years on syntheses and AC determination of chiral alkanes including [123]tetramantane, hexadeuterated neopentane, and trans‐perhydroazulene. Lastly, microscopic techniques and the crystalline sponge method are discussed as particularly promising approaches to revolutionize the field of stereochemical analysis. [ABSTRACT FROM AUTHOR]

Anisotropic NMR has gained increasing popularity to determine the structure and specifically the configuration of small, flexible, non‐crystallizable molecules. However, it suffers from the necessity to dissolve the analyte in special media such as liquid crystals or polymer gels. Generally, small degrees of alignment are also caused by an anisotropic magnetic susceptibility of the molecule, for example, induced by aromatic moieties. For this mechanism, the alignment can be predicted via density functional theory. Here we show that both residual dipolar couplings and residual chemical shift anisotropies can be acquired from natural products without special sample preparation using magnetically induced alignment. On the two examples of the novel natural product gymnochrome G and the alkaloid strychnine, these data, together with the predicted alignment, yield the correct configuration with high certainty. [ABSTRACT FROM AUTHOR]

Marine dinoflagellates produce remarkable organic molecules, particularly those with polyoxygenated long‐carbon‐chain backbones, namely super‐carbon‐chain compounds (SCCCs), characterized by the presence of numerous stereogenic carbon centers on acyclic polyol carbon chains. Even today, it is a challenge to determine the absolute configurations of these compounds. In this work, the planar structures and absolute configurations of two highly flexible SCCCs, featuring either a C69‐ or C71‐linear carbon backbone, gibbosols A and B, respectively, each containing thirty‐seven stereogenic carbon centers, were unambiguously established by a combined chemical, spectroscopic, and computational approach. The discovery of gibbosols A and B with two hydrophilic acyclic polyol chains represents an unprecedented class of SCCCs. A reasonable convergent strategy for the biosynthesis of these SCCCs was proposed. [ABSTRACT FROM AUTHOR]

Different examples of the application of quantum mechanical (QM) methods combined with experimental approaches, such as NMR spectroscopy and electronic circular dichroism (ECD), are reported to highlight their successful application in the determination of the stereochemical arrangement of organic compounds. A first part is dedicated to various examples and methodological studies based on the comparison of experimental NMR parameters (13C and 1H NMR chemical shifts, homonuclear and heteronuclear J coupling constants) and their related values calculated at the QM theory level, with particular applications in the assignment of the relative configuration of organic compounds. A final section is focused on the determination of the absolute configuration by the comparison of experimental and predicted NMR parameters and ECD spectra. [ABSTRACT FROM AUTHOR]

Residual dipolar couplings (RDCs) are amongst the most powerful NMR parameters for organic structure elucidation. In order to maximize their effectiveness in increasingly complex cases such as flexible compounds, a maximum of RDCs between nuclei sampling a large distribution of orientations is needed, including sign information. For this, the easily accessible one‐bond 1H–13C RDCs alone often fall short. Long‐range 1H–1H RDCs are both abundant and typically sample highly complementary orientations, but accessing them in a sign‐sensitive way has been severely obstructed due to the overflow of 1H–1H couplings. Here, we present a generally applicable strategy that allows the measurement of a large number of 1H–1H RDCs, including their signs, which is based on a combination of an improved PSYCHEDELIC method and a new selective constant‐time β‐COSY experiment. The potential of 1H–1H RDCs to better determine molecular alignment and to discriminate between enantiomers and diastereomers is demonstrated. [ABSTRACT FROM AUTHOR]

We present a method to use long‐range CH coupling constants to derive the correct diastereoisomer from the molecular constitution of small molecules. A set of 79 2JCH and 3JCH values collected from a single HSQMBC experiment on a sample of strychnine were used in the CASE‐3D (computer‐assisted 3D structure elucidation) protocol. In addition to the most commonly used 3JCH coupling constants, the subset of 32 2JCH values alone showed an excellent degree of configuration selection. The study is mainly based on comparison of DFT‐calculated 2,3JCH values with experimental ones, critical for the case of 2JCH. But the configuration selection also works well using 3JCH values predicted from a semi‐empirical Karplus‐based equation limited to H−C−C−C fragments. The robustness, shown using strychnine as a proof of concept, makes the J‐based CASE‐3D analysis a viable option for the application in fields such as peptide and carbohydrate research, organic synthesis, natural‐product identification and analysis, as well as medicinal chemistry. [ABSTRACT FROM AUTHOR]

We present the first asymmetric total synthesis and absolute configuration determination of (+)‐tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]‐bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven‐membered lactam. The side‐chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)‐tronocarpine was achieved through a 20‐step longest linear sequence from tryptamine. [ABSTRACT FROM AUTHOR]

Methylated analogues of isopentenyl diphosphate were synthesised and enzymatically incorporated into methylated terpenes. A detailed stereochemical analysis of the obtained products is presented. The methylated terpene precursors were also used in conjunction with various isotopic labellings to gain insights into the mechanisms of their enzymatic formation. [ABSTRACT FROM AUTHOR]

One undescribed homologous furanochromanone (1) featuring a 6/6/5/3 tetracyclic skeleton and four highly oxidized pyranochromanones (2 − 5), along with a set of four pyranochromanone stereoisomers [(±)- 6a and (±)- 6b ], were isolated from the leaves of Calophyllum membranaceum Gardn. Et Champ. Their structures were elucidated by using spectroscopic data, Snatzke's method, quantum-chemical calculations, and X-ray crystallographic analysis. The correlation of characteristic Cotton effects and specific chemical shifts with C-3 configuration provided a convenient approach to assign the C-3 configuration of 2,3-dimethylchromanones. The stereochemical assignments of 3-OH substituted pyranochromanones by quantum-based NMR methods following single/double MTPA derivatization were consistent with the ECD/NMR prediction, which verified the feasibility and reliability of the proposed empirical rule. The underlying mechanism was further clarified by conformational and molecular orbital analyses. Moreover, biological evaluation and binding assays demonstrated that compound 3 (K D = 0.45 μM) tightly binds to the TLR4–MD2 target, thereby inhibiting the TLR4/MyD88-dependent and -independent signal pathways. This study provides the first evidence that Calophyllum chromanones are a novel structural type of TLR4 inhibitors, exerting their anti-inflammatory effects by disrupting the binding between TLR4 and MD2. Nine undescribed chromanone acids were isolated from Calophyllum membranaceum and a convenient empirical approach using ECD/NMR strategy to access the C-3 configuration of these characteristic derivatives has been developed. Biological evaluation and binding assays elucidated the anti-inflammatory mechanism of these compounds targeting on TLR4−MD2. [Display omitted] • Nine undescribed chromanone acids were isolated from Calophyllum membranaceum. • Compound 1 is a novel furanochromanone featuring a 6/6/5/3 tetracyclic skeleton. • A convenient ECD/NMR rule was proposed for the determination of C-3 configuration. • The anti-inflammatory mechanism of targeting on TLR4–MD2 was elucidated. [ABSTRACT FROM AUTHOR]

Two new water-soluble phenanthroperylene quinones, gymnochrome H (2) and monosulfated gymnochrome A (3), as well as the known compounds gymnochrome A (4) and monosulfated gymnochrome D (5) were isolated from the deep-sea crinoid Hypalocrinus naresianus, which had been collected in the deep sea of Japan. The structures of the compounds were elucidated by spectroscopic analysis including HRMS, 1D 1H and 13C NMR, and 2D NMR. The absolute configuration was determined by ECD spectroscopy, analysis of J-couplings and ROE contacts, and DFT calculations. The configuration of the axial chirality of all isolated phenanthroperylene quinones (2–5) was determined to be (P). For gymnochrome H (2) and monosulfated gymnochrome A (3), a (2′S,2″R) configuration was determined, whereas for monosulfated gymnochrome D (5) a (2′R,2″R), configuration was determined. Acetylated quinones are unusual among natural products from an echinoderm and gymnochrome H (2) together with the recently reported gymnochrome G (1) represent the first isolated acetylated phenanthroperylene quinones.

Two pentameric foldamers, Q5 and Q5C‐S, containing a C−F bond were synthesized based on quinoline oligamide foldamers for the measurement of enantiomeric excess and for the determination of absolute configuration of chiral amines, diamines, amino alcohols, and α‐amino acid esters. Chiral induction of Q5 was triggered in situ when the chiral analytes reacted with the C−F bond in Q5 by a N‐nucleophilic substitution reaction, leading to a linear correlation between the CD amplitude at the region of quinoline chromophores and the ee values of the chiral analytes, which can be used for the ee determination of chiral analytes. Furthermore, the CD intensity of Q5C‐S containing a chiral motif at its C‐terminus enhances via remote, favorable chiral communication when the chiral induction was triggered in situ by chiral analytes at the N‐terminus matches the original helicity of Q5C‐S, but decreases via remote, conflicted chiral communication when the chiral induction is triggered in situ by chiral molecules at the N‐terminus mismatches the original one. The system can thus be used for determination of the absolute configuration of chiral analytes, given that the chirality of the chiral motif at the C‐terminus of Q5C‐S is known. [ABSTRACT FROM AUTHOR]

The diastereoselective synthesis of 3,5-disubstituted 1,4-oxazin - 2-ones, the valuable intermediates on the route to tetrahydroisoquinoline derivatives, was based on the Petasis reaction in which (R)-(−)- N -benzyl-2-phenylglycinol was used as the amine component. It was demonstrated that the configuration of the newly generated C3 stereogenic centers in synthesized compounds, as well as in other 3,5-disubstituted 1,4-oxazin-2-ones, could be established simply by 1H NMR spectral data analysis. The absolute configuration of the major isomer was additionally confirmed by single crystal X-ray analysis. Image 1 • Diastereoselective synthesis of 3,5-disubstituted-1,4-oxazin-2-ones. • The configuration of the newly generated C3 stereogenic center established by 1H NMR. • No derivatization or special measurements required for configuration assignment. • The absolute configuration of the (3 R ,5 R)-isomer confirmed by X-ray analysis. [ABSTRACT FROM AUTHOR]

A concise, scalable, six‐step (longest linear sequence) synthetic route to ovatodiolide scaffolds was developed for the first time. This protecting‐group‐free route features tandem ring‐opening metathesis/ring‐closing metathesis reactions to install the macrocycle‐fused butenolide ring and a tandem allylboration/lactonization to build the α‐methylene‐γ‐lactone. Our syntheses have enabled the determination of the hitherto unknown stereochemical configurations of this family of natural products. Preliminary tests of structure–activity relationships were conducted with four natural ovatodiolides and three analogues. Further assays indicated that the synthetic natural product isoovatodiolide can significantly decrease the population of hepatic cancer stem cells and reduce the tumorsphere‐forming capability of HepG2 cells. [ABSTRACT FROM AUTHOR]

Iriomoteolide‐2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG‐75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide‐2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide‐2a featured a late‐stage convergent assembly of three components by a Suzuki–Miyaura coupling, an esterification, and a ring‐closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2–5 as candidates for the correct structure. Accordingly, total syntheses of 2–5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2–5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide‐2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent‐5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent‐5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products. [ABSTRACT FROM AUTHOR]

The epimeric bisquinolizidines baptifoline and epibaptifoline are C‐13 hydroxylated derivatives of the well‐known lupine alkaloid anagyrine. We synthesized both compounds from 11‐allylcytisine and determined their uncertain configuration at the C‐13 stereocenter by NMR, chemical transformation, and X‐ray. The alcohol function was found to be in endo (α) position in baptifoline (configuration: 7R, 9R, 11R, 13R) and in exo (β) position in epibaptifoline (configuration: 7R, 9R, 11R, 13S). Baptifoline and epibaptifoline are C‐13 hydroxylated derivatives of the well‐known bisquinolizidine alkaloid anagyrine. We synthesized both epimers from 11‐allylcytisine and unambiguously determined their debated configuration at the C‐13 stereocenter by NMR, chemical transformation and X‐ray crystallography. [ABSTRACT FROM AUTHOR]

The mechanism of the cyclization is tunable by the choice of reagent, affording four different condensed heterocyclic ring systems. Keywords: Cycloaddition; Configuration determination; Diastereoselectivity; Domino reactions; Heterocycles; Molecular diversity EN Cycloaddition Configuration determination Diastereoselectivity Domino reactions Heterocycles Molecular diversity 3179 3179 1 10/18/23 20231013 NES 231013 The front cover illustrates the diastereoselective formation of condensed heterocyclic ring systems by domino reaction sequences. Cycloaddition, Configuration determination, Diastereoselectivity, Domino reactions, Heterocycles, Molecular diversity. [Extracted from the article]

The characteristic 1H NMR signals (H-7 and H 2 -9) are significant parameters that have been widely used to assess the relative configuration of H-7 and H-8 of 8,4′-oxyneolignans. However, many usual 8,4′-oxyneolignans cannot be accurately determined by existing NMR methods and no research considering their limitations was performed until now. In this study, the application scope of NMR methods was comprehensively studied and the Δ δ H9a–H9b methods have been extended to solve the majority of configuration determination difficulties. The accuracy of extended NMR methods was verified by anisotropic NMR (RCSA measurements), NMR calculation and diverse statistical analysis (MAE ΔΔ δ , CP3 and DP4+). Furthermore, the theoretical conformational analysis was performed to investigate the inherent limitations of existing NMR methods. This study could provide a valuable reference for determining the relative configuration of H-7 and H-8 in 8,4′-oxyneolignans and the relative configuration of 23 recently reported 8,4′-oxyneolignan derivatives should be reassigned as well. A valuable NMR methods studies for determining the relative configuration of H-7 and H-8 in diverse 8,4′-oxyneolignans and structural revision. [Display omitted] • The applicable scope of existing NMR methods has been clarified. • The applications scope of Δ δ H9a–H9b rules has been extended. • The accuracy of extended NMR methods was verified by multiple methods. • The explanation of limitations of existing NMR method was proposed. • The relative configuration of 23 reported 8,4′-oxyneolignans have been revised. [ABSTRACT FROM AUTHOR]

A terpene synthase from Nonomuraea coxensis was identified as (+)-1-epi-cubenol synthase. The enzyme is phylogenetically unrelated to the known enzyme of the same function that is widespread in streptomycetes. Isotopic labelling experiments were performed to unambiguously assign the NMR data and to investigate hydrogen migrations during terpene cyclisations. Epoxidations of (+)-1-epi-cubenol and of the plant derived compounds (-)-cubenol and (-)-1-epi-cubenol confirmed the structure of a natural product isolated from the brown alga Dictyopteris divaricata and allowed to conclude on its absolute configuration. The crystal structures of the epoxides from (+)- and (-)-1-epi-cubenol and the acid catalysed conversion into an isomeric ketone are reported., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

The conformational and stereodynamic properties of a pyrene‐substituted ethylthioporphyrazine (PzPy), promising as a dye for organic optoelectronic applications and light‐harvesting systems, have been investigated by DFT computations and variable‐temperature NMR and HPLC. In PzPy, rotation around the pyrene–macrocycle bond is hindered and the molecule displays atropisomerism, existing as a pair of enantiomers, thus representing the first chiral alkyl‐porphyrazine to be reported in the literature. The rotational barrier (ΔG‡ ≈ 22.0 kcal mol–1), measured by variable‐temperature HPLC experiments, allows chromatographic separation of the enantiomers on a chiral stationary phase below 0 °C, whereas racemization spontaneously occurs at room temperature. The absolute configurations of the eluted enantiomers were also determined by computational analysis of their electronic circular dichroism spectra. The influence of alkyl chain length and metal complexation on the molecular stereodynamic properties have also been investigated by studying its novel octylthio derivative (PzPy‐octyl) and PdII complex (PdPzPy), respectively. The latter also is the first example of a PdII–alkylthioporphyrazine complex. Given that PzPy has been used in the preparation of hybrid materials with nanocarbons for optoelectronic applications, the presence of an axial chirality element may play a key role in its interaction with semiconducting chiral nanotubes. [ABSTRACT FROM AUTHOR]